Biofilms are complex communities of microorganisms commonly found on a variety of substrates or surfaces that are moist or submerged (Musk et al., Curr. Med. Chem., 2006, 13: 2163; Donlan et al., Clin. Microbiol. Rev., 2002, 15: 167). Though primarily populated by bacteria, biofilms can also contain many different individual types of microorganisms, e.g., bacteria, archaea, protozoa and algae. The formation of biofilms can be thought of as a developmental process in which a few free-swimming (planktonic) bacteria adhere to a solid surface and, in response to appropriate signals, initiate the formation of a complex sessile microcolony existing as a community of bacteria and other organisms. Bacteria within biofilms are usually embedded within a matrix, which can consist of protein, polysaccharide, nucleic acids, or combinations of these macromolecules, and which protects the inhabiting organisms from antiseptics, microbicides, and host cells. It has been estimated, for example, that bacteria within biofilms are upwards of 1,000-fold more resistant to conventional antibiotics (Rasmussen et al., Int. J. Med. Microbiol., 2006, 296: 149).
Biofilms play a significant role in infectious disease. It is estimated that biofilms account for between 50-80% of microbial infections in the body, and that the cost of these infections exceeds $1 billion annually. A few of the diseases in which biofilms have been implicated include endocarditis, otitis media, chronic prostatitis, periodontal disease, chronic urinary tract infections, and cystic fibrosis. Persistent infections of indwelling medical devices also remains a serious problem for patients because eradication of these infections is virtually impossible. The persistence of biofilm populations is linked to their inherent insensitivity to antiseptics, antibiotics, and other antimicrobial compounds or host cells.
Deleterious effects of biofilms are also found in non-medical settings. For example, biofilms are a major problem in the shipping industry. Biofilms form on and promote the corrosion of ship hulls and also increase the roughness of the hulls, increasing the drag on the ships and thereby increasing fuel costs. The biofilms can also promote the attachment of larger living structures, such as barnacles, to the hull. Fuel can account for half of the cost of marine shipping, and the loss in fuel efficiency due to biofilm formation is substantial. One method of controlling biofilms is to simply scrape the films off of the hulls. However, this method is costly and time-consuming, and can promote the spread of troublesome non-native species in shipping waters. Another method involves the use of antifouling coatings containing tin. However, tin-based coatings are now disfavored due to toxicity concerns.
Agricultural production is also adversely affected by microorganisms growth on plants. The five main crops on which modern societies depend most heavily include corn, cotton, rice, soybeans, and wheat. All of these crops are affected in a deleterious manner by biofilm formation. Other valuable plants, such as those producing fruits and vegetables, plants grown for biomass, and forestry crops and ornamentals, are similarly affected. Given the steadily growing global population that is predicted to reach 6-9 billion persons by mid-century, the continual strain on existing and finite agricultural lands, and the recent diversion of valuable agricultural land from production of crops to production of biomass for fuels, new approaches are needed to control microbial effects in plants.
Due to the breadth of detrimental effects caused by bacterial biofilms, there has been an effort to develop small molecules that will inhibit their formation (Musk et al., Curr. Med. Chem., 2006, 13: 2163). The underlying principle is that if bacteria can be maintained in the planktonic state, they will not attach to a target surface and can be killed by a lower dose of microbicide. However, examples of structural scaffolds that inhibit biofilm formation are rare (Musk et al., Curr. Med. Chem., 2006, 13: 2163). The few known examples include the homoserine lactones (Geske et al., J. Am. Chem. Soc., 2005, 127: 12762), which are naturally-occurring bacterial signaling molecules that bacteria use in quorum sensing (Dong et al., J. Microbiol., 2005, 43: 101; Nealson et al., J. Bacteriol., 1970, 104: 313), brominated furanones isolated from the macroalga Delisea pulchra (Hentzer et al., Microbiology-Sgm, 2002, 148, 87), and ursene triterpenes from the plant Diospyros dendo (Hu et al., J. Nat. Prod., 2006, 69, 118).
In addition, bacteria have an unparalleled ability to overcome foreign chemical insult. For example, resistance to vancomycin, “the antibiotic of last resort,” has become more prevalent, and strains of vancomycin-resistant Staphylococcus aureus have become a serious health risk. It has been predicted that it is simply a matter of time before different bacterial strains develop vancomycin resistance, and the safety net that vancomycin has provided for decades in antibiotic therapy will no longer be available. Therefore, the identification of chemical architectures useful to inhibit biofilm development and/or overcome bacterial antibiotic resistance is needed.
Because of their natural resistance to antibiotics, phagocytic cells, and other biocides, biofilms are difficult, if not impossible, to eradicate. Therefore, the identification of compounds that control biofilms and/or bacterial growth in a variety of settings is of critical need.